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Structure of Macromolecular Machines using X-ray Crystallography and Electron Microscopy; Nonribosomal Peptide Synthetases

The Schmeing lab is interested in large macromolecular machines that perform important cellular processes. These enzymes often require supramolecular organization and complex architecture to function. For example, some enzymes use more than 100,000 atoms to make peptide bonds, while the proteases that break these bonds can be very small. Of course, these assemblies require regulation, processivity and fidelity, which contribute to their increased size. Our lab investigates both the manner by which cellular machines achieve these roles, and the mechanisms of their principal functions. To do this, we combine X-ray crystallography, electron microscopy and biochemical techniques.

Our main subject of study is nonribosomal peptide synthetases (NRPS). NRPSs are large macromolecular machines that catalyze peptide bond formation. Instead of making proteins, these megaenzymes produce a large variety of small molecules with important and diverse biological activity. For example, NRPSs synthesize anti-fungals, anti-bacterials, anti-virals, anti-tumourigenics, siderophores, and immunosuppressants including well-known compounds such as penicillin and cyclosporin. NRPSs use assembly line logic, with moving parts and dedicated active sites for each amino acid added to the peptide. NRPSs can be over 2 megadaltons in mass and are nature’s largest (and most fun!) enzymes.